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D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Gαi pathway in a human colonic epithelial cell model
No full textThe stereoisomers of lactate, L- and D- are not only metabolic substrates but also signalling molecules, capable of activating and signalling through its G protein-coupled receptor, Hydroxycarboxylic acid receptor 1 (HCAR1). These stereoisomers are both produced by the gut microbiota at millimolar concentrations creating a physiological environment for lactate-sensing unique to the gut yet, poorly understood. Here we identify a role for D-/L-lactate on intestinal barrier function. A human colonic epithelial cell model, Caco2, activated Gαi signalling in response to both L- and D-lactate, although L-lactate exhibited a more potent and rapid Gαi signal profile. When differentiated, apically but not basally treated D-/L-lactate enhanced tight junctions and reduced cell permeability, consistent with the apical localization of HCAR1. This improved barrier function occurred in a Gαi-dependent manner. In addition, apical lactate rescued the reduced intestinal barrier function induced by lipopolysaccharides. This work highlights the potential for D-/L-lactate supplementation in improving gut health
It’s all in the mix: Wasserstein classification and regression with mixed features
No full textProblem definition: A key challenge in supervised learning is data scarcity, which can cause prediction models to overfit to the training data and perform poorly out of sample. A contemporary approach to combat overfitting is offered by distributionally robust problem formulations that consider all data-generating distributions close to the empirical distribution derived from historical samples, where ‘closeness’ is determined by the Wasserstein distance. While such formulations show significant promise in prediction tasks where all input features are continuous, they scale exponentially when discrete features are present.
Methodology/results: We demonstrate that distributionally robust mixed-feature classification and regression problems can indeed be solved in polynomial time. Our proof relies on classical ellipsoid method-based solution schemes that do not scale well in practice. To overcome this limitation, we develop a practically efficient (yet, in the worst case, exponential time) cutting plane-based algorithm that admits a polynomial time separation oracle, despite the presence of exponentially many constraints. We compare our method against alternative techniques both theoretically and empirically on standard benchmark instances.
Managerial implications: Data-driven operations management problems often involve prediction models with discrete features. We develop and analyze distributionally robust prediction models that faithfully account for the presence of discrete features, and we
demonstrate that our models can significantly outperform existing methods that are agnostic to the presence of discrete features, both theoretically and on standard benchmark instances
Burn selection: how fire injury shaped human evolution
No full textThe mastery of fire transformed human evolution through advantages spanning diet, behaviour, physiology, and ecology. While these benefits are well established, here we highlight a previously overlooked cost — and selective pressure — unique to humans: high-temperature burn injury. Unlike other species, humans and their hominin ancestors have faced increased lifetime risk of burns, which we argue has driven genetic adaptation. Drawing on comparative genomic evidence across primates, we suggest that genes associated with burn injury response — relating to wound healing and inflammation — show signs of accelerated evolution in humans. We propose that recurrent exposure to burns acted as a selective force in our lineage, helping to explain both beneficial adaptations and paradoxical maladaptive responses to severe injury. By framing burns as an evolutionary pressure, the Burn Selection Hypothesis invites a re-evaluation of how fire shaped human biology and offers new perspectives for understanding both the evolutionary past and modern burn care
Anatomical variation of the pudendal nerve and related structures
No full textBackground and Objective: The pudendal nerve typically arises from sacral roots S2–S4 and gives rise to three main branches: inferior rectal, perineal, and dorsal genital nerves. However, conditions such as pudendal neuralgia and persistent genital arousal disorder demonstrate great variability in clinical course and therapeutic response. Anatomical variation may contribute to this variability by placing the nerve or its branches in vulnerable positions, leading to compression or traction. This scoping review examined pudendal nerve anatomical variations to better understand their role in pathophysiology and clinical outcomes.
Methods: A scoping review was conducted according to PRISMA-ScR guidelines to answer: “What are the anatomical variations of the pudendal nerve and related structures along its route?” Searches were conducted in MEDLINE and EMBASE databses, with manual screening. Studies included human anatomical investigations of pudendal nerve variations, regardless of method.
Key Findings and Limitations: Findings revealed substantial anatomical diversity in nerve roots, trunk, branches, and related structures, with detailed schematic illustrations developed. Limitations include methodological heterogeneity across studies, predominance of elderly cadaveric specimens, and lack of formal quality assessment.
Conclusions and clinical implications: Anatomical variation is a key factor in the development and persistence of pudendal nerve-related conditions. Understanding this variability is critical for diagnosis, surgical planning, and effective management. This review challenges assumptions of “typical anatomy” and offers context for refining decompression techniques and therapeutic strategies
Do amino-oxetanes resemble amides? A matched molecular pairs property and structural comparison
No full textOxetanes display properties comparable to ketone carbonyl groups and are increasingly explored as bi-oisosteres. However, does the comparison hold for the most common carbonyl derivatives: do amino-oxetanes resemble amides? Here, we present a matched molecular pair study of twelve 3-aryl-3-amino-oxetane and benzamide matched molecular pairs to assess their viability as isosteres. Across the surveyed physicochemical properties (pH stability, solubility, lipophilicity, clearance, permeability), amino-oxetanes exhibited broadly comparable profiles to their amide counterparts. Amino-oxetanes maintain both the H-bond acceptor and H-bond donor capabilities of analogous amides. These findings support the potential of amino-oxetanes as amide replacements. However, crystal structure analysis highlights the conformational differences and alternative exit vectors available through introduction of the oxetane ring. The preferred gauche conformation makes the torsion angle and exit vectors of amino-oxetanes more similar to sulfonamides, and therefore better like-for-like topological replacements. Overall, amino-oxetanes present an attractive design option to modulate physi-cochemical properties and chemical topology
A systematic review, meta-analysis and meta-regression of the impact of PCSK9 inhibitors on carotid intima-media thickness and the association with lipid parameters
No full textObjective
We assessed the impact of PCSK9 inhibitors (PCSK9i) on carotid intima-media thickness (cIMT) and their interplay with lipid profile parameters.
Methods
A systematic review was conducted in accordance with the PRISMA 2020 guidelines. The primary endpoint was cIMT reduction in millimeters by the end of treatment. A meta-regression analysis was performed, examining the influence of demographic, imaging, and biochemical parameters on cIMT outcomes. Heterogeneity exploration was conducted via leave-one-out and Baujat plot analysis.
Results
Four randomized controlled trials comparing PCSK9i plus statin versus placebo plus statin, and two single-arm studies were included, enrolling 607 patients and 2175 carotid segments. Pooled analysis demonstrated a significant reduction in cIMT from baseline to completion of PCSK9i therapy; mean difference (MD) -0.03 (95% CI: -0.05 to -0.01) (I2=95.4%, p<0.01). Following exploration and mitigation of heterogeneity, this reduction persisted; MD -0.01 (95% CI: -0.02 to -0.01) (I2=0%, p=0.59). Initially, the comparison between PCSK9i and placebo yielded a non-significant reduction in cIMT by the end of follow-up, favouring PCSK9i; MD -0.04 (95% CI: -0.10 to 0.03) (I2=98.6%, p<0.01). However, following heterogeneity adjustment, the effect estimate reached statistical significance, demonstrating a consistent cIMT reduction with PCSK9i; MD -0.01 (95% CI: -0.02 to -0.01) (I2=52%, p=0.12). Meta-regression analysis displayed associations between baseline cIMT (β=-0.45, p<0.01), HDL (β=1.92, p<0.01) and cIMT outcomes. Pooled between-group cIMT differences showed moderate correlations with the respective differences in total (r=0.69) and LDL cholesterol (r=0.59) across the included studies.
Conclusions
This review provides evidence supporting a potential association between PCSK9i treatment and cIMT reduction, with observed correlations involving total and LDL cholesterol indicating a lipid-mediated vascular response. Nonetheless, these findings warrant cautious interpretation given the substantial heterogeneity, partly driven by baseline differences in cIMT and lipid profiles. Future studies should ensure baseline comparability in vascular and biochemical parameters to strengthen causal inferences
Parallelisation of partial differential equations via representation theory
No full textIncorporating symmetries into the numerical solution of differential equations has been a mainstay of research over the last 40 years, however, one aspect is less known and under-utilised: discretisations of partial differential equations that commute with symmetry actions (like
rotations, reflections or permutations) can be decoupled into independent systems solvable in parallel
by incorporating knowledge from representation theory. We introduce this beautiful subject via a crash course in representation theory focussed on hands-on examples for the symmetry groups of the square and cube, and its utilisation in the construction of so-called symmetry-adapted bases. Schur’s lemma, which is not well-known in applied mathematics, plays a powerful role in proving sparsity of resulting discretisations and thereby showing that partial differential equations do indeed decouple.
Using Schr¨odinger equations as a motivating example, we demonstrate that a symmetry-adapted basis leads to a significant increase in the number of independent linear systems. Counterintuitively, the effectiveness of this approach is in fact greater for partial differential equations with less symmetries, for example a Schr¨odinger equation where the potential is only invariant under permutations, but not under rotations or reflections. We also explore this phenomenon as the dimension of the partial differential equation becomes large, hinting at the potential for significant savings in high-dimensions
Experimental generation of non-uniform surface temperature distributions in high-speed flow
No full textThis study presents prediction and experimental measurement of non-uniform surface temperature distributions on a flat plate test article for a flow control method. The test article features strips of materials (copper and MACOR) with dissimilar thermal properties interacting with a developing boundary layer to establish a passively controlled, non-uniform temperature profile. Experiments with a pre-heated model are conducted within the Imperial College supersonic wind tunnel at Mach 2.75. Infrared thermography is used for surface temperature measurements. Results from the experiments confirm the passive surface temperature control, demonstrating temperature variations between the strips. Furthermore, the physics-informed thermal model, with boundary conditions derived from actual wind tunnel conditions, predicts non-uniform surface temperature distributions that quantitatively align with the experimental results. Higher temperature differences between the strips of dissimilar materials can be achieved by increasing the difference between the recovery temperature and the initial temperature. These results validate the proposed actuation method’s ability to generate significant spanwise surface temperature variations. This validation of
the actuation method serves as a prerequisite for future experimental campaigns, which will focus on measuring the induced velocity streaks and assessing their efficacy for boundary layer transition delay in hypersonic environments
Safeguarding planetary health: the contribution of community health workers to climate stability, global equity, and social justice
No full textPlanetary health, the interdependence of human health and natural systems, is under severe threat. Climate breakdown, biodiversity loss, and chemical pollution are driving overlapping crises that already undermine health and equity. The Lancet Commission on planetary health warned in 2015 that “human health and human civilisation depend on flourishing natural systems”. Yet, progress remains too slow; land and marine protections are insufficient, global dietary shifts are lagging, and reliance on fossil fuels persists. Public awareness has grown, spurred by influential voices such as those of Sir David Attenborough, who distilled six interconnected actions from scientific consensus: rewilding land and oceans, transitioning to renewable energy, reducing meat consumption, establishing marine reserves, stabilising human population by bringing growth to zero through education and equity, and prioritising wellbeing within ecological limits over the growth of economic output and resource throughput. Community health workers (CHWs) are health-care providers who live in the community they serve and receive less formal education and training than professional health-care workers, such as nurses and doctors. In this Viewpoint, we argue that trusted, hyperlocal, and globally present CHWs are a largely overlooked workforce in tackling the climate crisis, despite already doing work in adapting to and mitigating climate change. By embedding planetary health within their remit, CHWs can link health, justice, and climate resilience in practical ways, offering one of the most feasible pathways to accelerate progress. Redirecting even a small proportion of fossil-fuel subsidies towards strengthening CHWs to improve global health access could close the global health-workforce gap, reduce gender inequities, redress colonial imbalances, and deliver both climate mitigation and adaptation to ensure a liveable future for all
Hydraulic endorectal actuator for prostate radiotherapy reduces variations in motion in a silicone rectal phantom
No full textBackground: The accuracy and morbidity of prostate cancer radiotherapy are influenced by unpredictable variations in rectal filling and patient motion. We developed a soft robotic hydraulic endorectal actuator that aims to reduce rectal motion and retract the rectum to restore the anorectal angle, improve target accuracy, and reduce toxicity during prostate cancer radiotherapy. The ability of the endorectal actuator to stabilize the rectum and improve prostate radiotherapy outcomes has not yet been assessed. This study evaluates the actuator’s performance in a simulated rectal phantom.
Methods: We fabricated a rectal phantom using silicone and motor-controlled elastic ribbons to simulate muscle tone and control the phantom diameter. The rectal compliance of the phantom was validated using a barostat balloon and was deliberately set low to simulate a high resistance to distension to challenge the actuator’s capabilities. We assessed the actuator’s ability to (1) resist dynamic peristaltic forces and (2) reproduce the rectal position and anorectal angle from varying initial displacements. The anterior–posterior rectal diameter and anterior rectal wall (ARW) displacements were measured using video tracker software.
Results: The phantom demonstrated a rectal compliance of 4.19 ml/mmHg within the 40 ml–60 ml volume range, meeting the low-compliance target. During dynamic compression, the endorectal actuator reduced the change in the anterior–posterior diameter and ARW displacement from 25 mm and 15 mm, respectively, to less than 5 mm in both. The actuator reduced the increase in rectal volume from 132.3 cm3 (control) to 59.7 cm3 (actuator). When the phantom was translated anteriorly, the actuator reduced the anorectal angle deviation from +12° to +2° and anterior displacement of the ARW from 13 mm to 4 mm.
Conclusion: Within this rectal phantom, the endorectal actuator reduced the variations in rectal motion. These findings suggest that the actuator may improve target accuracy and reduce radiation-induced toxicity in prostate radiotherapy, pending in vivo validation of the results